The chemical biology and biomedical sciences are undergoing a new era of vigorous development due to the rapid discovery of new protein targets and unveiling of their biological importance. Combinatorial chemistry has emerged as a tool for the generation and screening of diverse libraries of compounds with potential use as ligands that recognize peptide or protein targets with high specificity and affinity. For example, combinatorial chemistry techniques have been applied to the preparation of peptide libraries with modular chemical diversity and favorable binding activity. Among them, macrocyclic peptides which have enhanced conformational constraint and binding affinity are widely recognized for exploring ligand-receptor interactions. Several general methods have been successfully developed to construct the macrocyclic ring systems.
Recent efforts have contributed to the creation of non-natural sequence-specific peptidomimetics. These peptidomimetics are developed based on the mimicry of peptide primary structure and modified peptide backbone for the introduction of diverse functional side chains. Compared with natural peptides, peptidomimetics possess enhanced protease-resistance and chemodiversity, as well as improved bioavailability. The past decade has witnessed significant progress in the development of biomimetic oligomers, including β-peptides, peptoids, α-aminoxy-peptides, α/β-peptides, azapeptides, etc. However, up to date only a handful of peptidomimetic libraries have been systematically investigated for protein ligand identification. The development of macrocyclic peptidomimetic combinatorial libraries is even more scarce. Thus, there remains an unmet need to identify macrocyclic peptidomimetic ligands that recognize peptide or protein targets with high specificity and affinity.